Interdigitated electrode (IDE) arrays with nanometer-scale gaps have been utilized to enhance the sensitivity of affinity-based detection. The geometry of nanogap IDEs was first optimized on the basis of simulations of the electric field and current density. It was determined that the gap (G) between the electrodes was the most important geometric parameter in determining the distribution and strength of the electric field and the current density compared to the width (W) and height (H) of the IDEs. Several devices were materialized and analyzed for their sensitivity to the electrochemical environment using faradic electrochemical impedance spectroscopy (EIS) as the detection technique. Nanogap optimized IDEs were then employed as biosensors for the label-free, affinity-based detection of antitissue transglutaminase antibodies (αtTG-Abs), a biomarker for the detection of autoimmune disorder celiac sprue, triggered by ingesting gluten. The label-free biosensor assay was found to be less sensitive compared to on-chip ELISA. Gold nanoparticles (GNPs) were then employed to improve the sensitivity of the nanogap IDE-based biosensor. With GNPs, the transducer sensitivity increased by 350% over that of label-free detection. The suitability of nanogap IDEs as biosensor transducers for EIS in label-free and GNP-labeled formats was established. The immunobiosensor assay detection sensitivity with the GNPs was found comparable to ELISA.